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ABSTRACT: The intestinal mucosa creates a connection between the gut microbiota and the host. This study aimed to modify the gut microbiota of broiler chickens by in ovo stimulation with xylo-oligosaccharide (XOS) and manno-oligosaccharide (MOS) prebiotics and to determine the changes occurring in specific gut segments. Three hundred incubated eggs of Ross 308 broiler chickens on the 12th d of incubation were injected with: saline (control), xylotriose (XOS3), xylotetrose (XOS4), mannotriose (MOS3) or mannotetrose (MOS4). Tissue and digesta samples were collected post-mortem from 8 randomly selected individuals from each group, on d 42 after hatching. Gene expression analysis in the cecum and ileum was performed by RT-qPCR for a panel of genes: innate immune response genes (IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-17, IL-1β, IFNγ, IFNβ), nutrient sensing and nutrient transport genes (FFAR2, FFAR4, GLUT1, GLUT2, GLUT5), host defence peptides (AvBD1, CATHL2), and barrier function genes (MUC6, CLDN1, TJAP). The relative abundance of bacteria was determined by qPCR for individual bacteria (Akkermansia muciniphilla, Bifidobacterium spp., Clostridium difficile, Escherichia coli, Faecalibacterium prausnitzii, and Lactobacillus spp.). Stimulation with prebiotics caused changes in the abundance of bacteria especially Lactobacillus spp. and Bifidobacterium spp. in the cecum. The abundance of both genera increased in each study group compared to the control group. The highest abundance of Bifidobacterium spp. in the ileum was found in the MOS3 group compared to the control group. There were changes in the XOS4 and MOS3 groups in the expression of: FFAR4, GLUT1, AvBD1, CATHL2, IL-2, IL-12, and IL-17 in the caecum. In conclusion, in ovo administration of prebiotics increased intestinal colonization by bacteria. The prebiotics influenced gene expression levels via changes in the gut microbiota.

ABSTRACT: A healthy gut is one of the main factors influencing bird response. Over the years, efforts have been made to improve intestinal health. One of the supporting methods may be enriching the diet with bioactive ingredients, including sodium butyrate (SB). One of the possible ways of administering such supplementation is in ovo technology. Over the years, research has shown that administering bioactive substances this way has a positive effect on the health status of chickens. The current study aimed to modify the gut microbiota of broiler chickens by in ovo stimulation on d 12 of egg incubation with SB and to determine the changes occurring in intestines. One thousand eggs were incubated and injected with 0.1, 0.3, or 0.5% SB on d 12 of incubation. The control group was injected with physiological saline. Samples collected for analysis were obtained postmortem from 42-day-old ROSS 308 broiler chickens. Growth performance parameters were also monitored during broiler rearing. Gene expression analysis showed significant changes in the levels of IL4, IFNγ, AvBD1, TJAP and MUC6 genes in the ileum. However, the IL8, MUC2 and MUC6 genes were significantly expressed in the cecal mucosa. These changes depended on the administered dose of butyrate. There was no effect of in ovo administration of various doses of SB on digesta pH, SCFA level and histological parameters. However, a significant increase in Bifidobacterium bacteria was detected in the ileum after administration of a dose of 0.5% SB and in the cecum after administration of a dose of 0.3%. Administration of SB in ovo has the potential to support intestinal health in poultry. The effects depend on the administered dose, while the results indicate a dose of 0.3% as the most optimal.

In pediatric acute lymphoblastic leukemia (ALL), mutations/deletions affecting the TP53 gene are rare at diagnosis. However, at relapse about 12% of patients show TP53 aberrations, which are predictive of a very poor outcome. Since p53-mediated apoptosis is an endpoint for many cytotoxic drugs, loss of p53 function frequently leads to therapy failure. In this study we show that CRISPR/Cas9-induced loss of TP53 drives resistance to a large majority of drugs used to treat relapsed ALL, including novel agents such as inotuzumab ozogamicin. Using a high-throughput drug screen, we identified the histone deacetylase inhibitor romidepsin as a potent sensitizer of drug responsiveness, improving sensitivity to all chemotherapies tested. In addition, romidepsin improved the response to cytarabine in TP53-deleted ALL cells in vivo. Together, these results indicate that the histone deacetylase inhibitor romidepsin can improve the efficacy of salvage therapies for relapsed TP53-mutated leukemia. Since romidepsin has been approved for clinical use in some adult malignancies, these findings may be rapidly translated to clinical practice.

Theoretical background: Incorporating behavioral analysis into finance allows for finding responses to many questions that researchers have not been able to answer by relying on assumptions characteristic of the traditional, normative approach. One of the areas where recently the achievements of behavioral finance have been used to analyze selected problems is public finance. In this article, we use the achievements of psychology, incorporating them into public finance, which allows us to shed new light on decisions made by public managers in Poland. Purpose of the article: The aim of this paper is to present the reasons why local governments do not buy insurance that would protect them against potential losses resulting from the occurrence of a catastrophic event. In this paper, we rely on responses from 303 municipalities, following the premise that an obvious way to learn about motives, constraints, and the decision-making process is to ask decision-makers. Research methods: This paper examines the influence of behavioral determinants and the level of tax revenue per capita on the decisions made by public managers. The CART method was used for this purpose. The necessary empirical data were obtained through a CAWI survey conducted in 2020 between August 1 and September 21 by a consortium of two research agencies: Biostat Research & Development Sp. z o.o. and Biostat Sp. z o.o. Main findings: The analysis conducted in this paper demonstrates that behavioral factors significantly impact public managers' decisions not to purchase catastrophe insurance. Our results confirm the significant role of a decision maker's traits, judgments, views, feelings, and experiences in the decision-making process.

Introduction: Under-triage increases patients’ risks for morbidity and mortality, whereas over-triage limits the resources available to sicker patients. This study aimed to determine the rates as well as associated factors of under-triage and over-triage in emergency department (ED), based on Emergency Severity Index (ESI) triage system. Methods: In this retrospective cross-sectional study, triage level of ED patients based on the ESI version 4, was studied during a 9-month period in 2019. Patients’ ESI level, which were examined by triage nurses were reevaluated by 3 emergency physicians and the rate of correct, under-, and over-triage as well as their associated factors were analyzed. Results: 1000 cases of triage were evaluated. Triage was correct in 69.1% of cases. The rate of under-triage was 4.9%, and that of over-triage was 26.0%. Over-triage was significantly more common among patients aged 18–30 years than for those aged ≥65 years (adjusted odds ratio [OR] = 1.73; 95% confidence interval [CI]: 1.07–2.81; p = 0.026); those with traumatic injuries (adjusted OR = 1.80; 95% CI: 1.29–2.52; p = 0.001); those arriving at the hospital during the evening shift (adjusted OR = 1.42; 95% CI: 1.01–2.0; p = 0.046); patients who were hospitalized (adjusted OR = 0.35; 95% CI: 0.22–0.54; p < 0.001); and those with severe pain (adjusted OR = 0.28; 95% CI: 0.10–0.84; p = 0.023). Younger age was also significantly associated with under-triage. Patients aged 18–30 years were under-triaged more often than those aged ≥65 years (adjusted OR = 3.05; 95% CI: 1.16–8.00; p = 0.023). Conclusions: Over-triage was substantially more common than under-triage in Vajira Hospital. Factors associated with over-triage were younger age, traumatic injury, arrival time, hospital admission, and severe pain. Younger age was the only factor related to under-triage.

The hedgehog (Hh) signalling pathway plays a key role in both embryonic and postnatal development of the intestine and is responsible for gut homeostasis. It regulates stem cell renewal, formation of the villous–crypt axis, differentiation of goblet and Paneth cells, the cell cycle, apoptosis, development of gut innervation, and lipid metabolism. Ligands of the Hh pathway, i.e., Indian hedgehog (Ihh) and Sonic hedgehog (Shh), are expressed by superficial enterocytes but act in the mesenchyme, where they are bound by a Patched receptor localised on myofibroblasts and smooth muscle cells. This activates a cascade leading to the transcription of target genes, including those encoding G1/S-specific cyclin-D2 and -E1, B-cell lymphoma 2, fibroblast growth factor 4, and bone morphogenetic protein 4. The Hh pathway is tightly connected to Wnt signalling. Ihh is the major ligand in the Hh pathway. Its activation inhibits proliferation, while its blocking induces hyperproliferation and triggers a wound-healing response. Thus, Ihh is a negative feedback regulator of cell proliferation. There are data indicating that diet composition may affect the expression of the Hh pathway genes and proteins, which in turn, induces changes in mucosal architecture. This was shown for fat, vitamin A, haem, berberine, and ovotransferrin. The Hh signalling is also affected by the intestinal microbiota, which affects the intestinal barrier integrity. This review highlights the critical importance of the Hh pathway in shaping the intestinal mucosa and summarises the results obtained so far in research on the effect of dietary constituents on the activity of this pathway. [ABSTRACT FROM AUTHOR]

The growing interest in high-energy emulsification is a result of its scalability, which is important from an industrial perspective and allows for a more reproducible and efficient production of pharmaceutical formulations. The aim of this study was to evaluate the effect of composition, mainly a fixed surfactant/cosurfactant (Smix) ratio, their concentration, and the parameters of high-pressure homogenization (HPH) processing on the quality and stability of ophthalmic fluconazole-loaded nanoemulsions. After a physicochemical analysis of nanoemulsions containing 20% w/w of oil, as optimal conditions for the HPH process, three cycles at a pressure of 1000 bar were established, obtaining formulations with an average droplet diameter size in the range of 80.63–129.68 nm and PDI values below 0.25. While it was expected that an increasing cosurfactant concentration decreased the droplet size, in the case of formulations containing Tween 20 and 10% w/w of cosurfactants, “over-processing” was observed, identified by the droplet size and polydispersity index increase. Consecutively, the selected formulations were evaluated for in vitro drug release in Franz’s cell, antifungal activity, and 30-day stability using NMR spectroscopy. An antifungal activity test showed no significant difference in the antifungal activity between optimal fluconazole-loaded nanoemulsions and a 0.3% aqueous drug solution, but previously, research showed that prepared formulations were characterized by a higher viscosity and satisfactory prolonged release compared to a control. In a 30-day stability study, it was observed that higher HLB values of the used surfactants decreased the stability of the formulations in the following order: Kolliphor EL, Tween 80, Tween 20. The NMR spectra confirmed that Kolliphor EL-based formulations ensured the higher stability of the nanoemulsion composition in comparison to Tween 80 and a better stabilizing effect of propylene glycol as a cosurfactant in comparison to PEG 200. Therefore, the optimization of HPH technology should be focused on the selection of Smix and the Smix:oil ratio in order to prepare stable formulations of high quality.

Pharmacotherapy is the main treatment method for depression, bipolar disorder, and schizophrenia. As such, in many countries the potential service of pharmacist’s, especially for medicine review, active participation in improving patient compliance, and cooperation with mental health clinical pharmacists, within an interdisciplinary healthcare team, are considered significant elements of healthcare. This article uses available references to identify the potential role and describe the types of activities undertaken by pharmacists as one of the groups of specialists supporting the healthcare of psychiatric patients. The participation of pharmacists in screening tests for example towards depression, their role in education, and delivering comprehensive information about medication to patients and other healthcare workers, their role in the improvement of primary prevention and health promotion as well as the participation in actions connected with changing patient’s lifestyle have been described. Special attention was placed on the role of pharmacists in monitoring of pharmacotherapy with the goal to improve patient compliance on the use of antidepressants and participation in evaluation of laboratory test results and analysis of medication prescription in hospitals. Pharmacists should also consider/ take up pharmaceutical care of patients with psychiatric illnesses as an extended area of activity. The changing the attitude towards professional practice from a supplier of medicinal products to a specialist providing the best pharmacotherapy and safety for patients, will consequently increase the level of responsibility of pharmacies and pharmacists. This requires a change in perception of one's own role, an organizational and functional approach to exercising this area of pharmaceutical care. In addition, there is an urgent need to develop new standards, establish cooperation with other healthcare professions, and define strategies for the promotion/ marketing of pharmaceutical care. Restoration of the expected role of the pharmacy will be achieved only if pharmacists accept their social mandate to ensure safe and effective pharmacotherapy for individual patients, which was particularly presented in this paper for patients with mental health problems.

Abstract Background Advantages of translocation of recombinant proteins to the periplasm in Escherichia coli include simplified downstream processing, and improved folding and in vivo activity of the target protein. There are, however, problems encountered in the periplasmic production that can be associated with the incorrect formation of disulfide bonds, incomplete cleavage of the signal peptide, and proteolytic degradation. A common strategy used to overcome these difficulties involves manipulating the cellular levels of proteases and periplasmic folding assistants like chaperones, signal peptide peptidases or thiol-disulfide oxidoreductases. To date, this has been achieved by plasmid-based over-expression or knockouts of the relevant genes. Results We changed the translation efficiencies of five native E. coli proteins, DsbA, DsbB, Skp, SppA, and DegP, by modifying the strength of their ribosome binding sites (RBS). The genomic RBS sequences were replaced with synthetic ones that provided a predicted translation initiation rate. Single- and double-gene mutant strains were created and tested for production of two pharmaceutically relevant proteins, PelB-scFv173–2-5-AP and OmpA-GM-CSF. Almost all the single-gene mutant strains showed improved periplasmic production of at least one of the recombinant proteins. No further positive effects were observed when the mutations were combined. Conclusions Our findings confirm that our strain engineering approach involving translational regulation of endogenous proteins, in addition to plasmid-based methods, can be used to manipulate the cellular levels of periplasmic folding assistants and proteases to improve the yields of translocated recombinant proteins. The positive effects of SppA overexpression should be further investigated in E. coli.

The estimation of electric power utilization, its baseload, and its heating, light, ventilation, and air-conditioning (HVAC) power component, which represents a very large portion of electricity usage in commercial facilities, are important for energy consumption controls and planning. Non-intrusive load monitoring (NILM) is the analytical method used to monitor the energy and disaggregate total electrical usage into appliance-related signals as an alternative to installing multiple electricity meters in the building. However, despite considerable progress, there are a limited number of tools dedicated to the problem of reliable and complete energy disaggregation. This paper presents an experiment consisting in designing an electrical system with electrical energy receivers, and then starting NILM disaggregation using machine learning algorithms (MLA). The quality of this disaggregation was assessed using dedicated indicators. Subsequently, the quality of these MLA was also verified using the available BLUED data source. The results show that the proposed method guarantees non-intrusive load disaggregation but still requires further research and testing. Measurement data have been published as open research data and listed in the literature section repository.

The combination of statins and fibrates in the treatment of lipid abnormalities effectively regulates individual lipid fraction levels. In this study, the screening and assessment of the physicochemical properties of simvastatin-fenofibrate solid dispersions were performed. Fenofibrate and simvastatin were processed using the kneading method in different weight ratios, and the resulting solid dispersions were assessed using differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), Fourier-transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), contact angle, as well as dissolution tests. The obtained results confirmed the formation of a simple eutectic phase diagram, with a eutectic point containing 79 wt% fenofibrate and 21 wt% simvastatin, lack of chemical interactions between the ingredients, and simvastatin impact on improving fenofibrate dissolution profile, due to the formation of crystalline solid dispersions by the kneading method.

The presence of androgen (AR) and estrogen (ER) receptors has been demonstrated both in normal perianal (hepatoid) glands and in perianal tumors. The aim of this study was to demonstrate the relationship between the expression of AR and ER in perianal gland tumors and the effectiveness of antihormonal treatment. The study was performed on 41 male dogs with neoplastic lesions of the anal region. Histopathological evaluation of the lesions revealed 24 adenomas, 12 epitheliomas, and five carcinomas. Treatment was administered orally with tamoxifen at a dose of 1 mg/kg BW and cyproterone acetate at a dose of 5 mg/kg. Tumor diameters were measured regularly with calipers and recorded in millimeters starting with the measurement before treatment, and then after 1, 2, 3, 6, 12, 18, and 24 months of therapy. The results show that hepatoid adenomas that are characterized by high expression of AR and ER receptors respond positively to antihormonal therapy, resulting in complete tumor regression. For locally malignant hepatoid epitheliomas and carcinomas with low expression of AR and ER receptors, antihormonal therapy makes it possible to reduce the size of the tumor, but does not make it possible to cure it completely.